Various deoxy derivatives of kanamycin A, B and C are already known as the semi-synthetic aminoglycosidic antibiotics which are derived from the kanamycins. These known deoxy derivatives of the kanamycins A, B and C have usefully high antibacterial activities, but the antibacterial spectra of these known deoxy-derivatives of the kanamycins are of different ranges. These known deoxykanamycin derivatives are possible to become inactive against such new resistant strains of bacteria which will occasionally occur in future. Accordingly, it is always demanded that new, antibacterial compounds having any more excellent properties than the known antibacterial kanamycin derivatives should be produced newly and provided for uses in therapeutic treatment of bacterial infections.
We, the present inventors, had an expectation that if we would succeed in synthetizing such a new kanamycin A derivative having the 3'-hydroxyl group replaced by a fluoro group, namely 3'-fluoro-3'-deoxykanamycin A, this new kanamycin A compound should be active against some kanamycin-resistant strains of bacteria which are already known and also against some another resistant strains which will possibly occur in future.
With such expectation, we made our efforts to synthetize 3'-fluoro-3'-deoxykanamycin A, and as a result, we succeeded in synthetizing 3'-fluoro-3'-deoxykanamycin A as a semi-synthetic aminoglycosidic antibiotic, of which the process for production, physico-chemical properties and antibacterial spectra have been disclosed in Japanese patent application No. 161615/84 (filed Aug. 2, 1984 in Japan) which corresponds to U.S. patent application Ser. No. 758,819; and European patent application No. 85 401575.7.
We made our further research in attempt to synthetize a new compound, 3'-fluoro-3'-deoxykanamycin B and we succeeded in synthetizing 3'-fluoro-3'-deoxykanamycin B according to such a synthetic process as described hereinafter, wherein a known compound, 6'-N, 4'-O-carbonyl-4",6"-O-cyclohexylidene-1,2',3,3"-tetra-N-tosylkanamycin B (the compound disclosed as an N,O-protected kanamycin B derivative in Japanese patent application first publication "kokai" No. 63993/81; U.S. Pat. No. 4,349,666; and the "Nippon Kagaku Kaishi" 1982, No. 10, pages 1706-1712) was employed as a starting compound.
We have found that 3'-fluoro-3'-deoxykanamycin B has remarkable antibacterial activities against various gram-positive and gram-negative bacteria, including the resistant bacteria (Japanese patent application No. 262700/84; Japanese patent application first publication "Kokai" No. 140597/86).
However, it has been found that the new compound, 3'-fluoro-3'-deoxykanamycin B having a hydroxyl group at the 4'-position exhibits rather a low antibacterial activity against some resistant strains of bacteria capable of producing a phosphorylating enzyme and/or an adenylating enzyme which can react with the 4'-hydroxyl group. Examples of such resistant strains of bacteria are Staphylococcus aureus Ap 01 and Staphylococcus epidermidis 109.
We, therefore, had an expectation that if we would succeed in synthetizing such a new 3'-deoxy-3'-fluorokanamycin B derivative which has the 4'-hydroxyl group eliminated, namely a kanamycin B derivative identifiable as 3',4'-dideoxy-3'-fluorokanamycin B, this new 4'-deoxy-derivative of 3'-deoxy-3'-fluorokanamycin B should be active against a variety of resistant strains of bacteria of the sorts as mentioned above. As a result of our further researches, we have now succeeded in synthetizing 3',4'-dideoxy 3'-fluorokanamycin B as a new compound, and we have discovered that the new compound, 3',4'-dideoxy-3'-fluorokanamycin B now produced exhibits an enhanced antibacterial activity against a wide variety of bacteria, as compound with the 3'-fluoro-3'-deoxykanamycin B.